ABSTRACT Germinal matrix-intraventricular hemorrhage (GM-IVH) is a major complication of premature birth, occurring in up to 45% of very low birthweight neonates (<1500 g) due to fragility of immature blood vessels within the germinal matrix. GM-IVH can also lead to hydrocephalus (HCP) and increased intracranial pressure, which further induces inflammation and brain tissue injury. Though neonatal GM-IVH and HCP are increasingly common due to the rising survival rate of preterm births, there are no established biomarkers or guidelines for their treatments to prevent brain injury. Preterm infants with GM-IVH/HCP are vulnerable to alterations in cerebral blood flow (CBF) because they have impaired cerebrovascular autoregulation. However, there are no reliable functional imaging methods at the bedside of neonatal intensive care units (NICUs) for repeatedly assessing either degree of cerebral injury or effectiveness of interventions. Near-infrared spectroscopy and tomography technologies have been used for decades as noninvasive bedside tools for continuous monitoring of cerebral blood oxygen saturation (StO2). However, most systems lack the combination of spatial resolution and wide field- of-view (FOV) to image distributed brain functions and discriminate the brain signal from overlaying scalp and skull. A few high-density tomographic systems use numerous discrete sources and detectors coupled with fiber bundles to a head cap. However, adjusting and maintaining a stable optical coupling of numerous fibers to a small fragile neonatal head (i.e., a contact measurement) is labor-intensive and poses great challenges to head cap design with safety concern. To overcome these limitations, we propose to develop a novel, noncontact, high-density-detection (using a CCD/CMOS camera), multi-wavelength speckle contrast diffuse correlation tomography (MW-scDCT) system to accommodate fast, high-resolution, functional imaging of both CBF and StO2 over a large FOV on the neonatal head. The MW-scDCT will be rigorously calibrated and optimized using standard tissue phantoms (Aim 1). In vivo calibration/evaluation will be conducted against MRI and histological examination in an IVH/HCP model of neonatal piglets who preserve great similarities with human neonates (Aim 2). A pilot clinical observational study will be performed in preterm neonates with GM-IVH/HCP under standard of care in the NICU (Aim 3). Cerebral hemodynamics/metabolism, cerebrovascular autoregulation, and cerebral functional connectivity will be analyzed from serial functional images taken over several weeks after birth. We hypothesize that cerebral hemodynamic/metabolic alterations detected by MW-scDCT correlate with progression of brain injury after GM-IVH/HCP and recovery after treatment. Multiple parameters will provide more comprehensive assessments of neonatal brain injury/recovery compared to a single parameter alone. This study will fulfill a critical need in the field of neonatology to provide objective measures/biomarkers to guide timing of treatment for GM-IVH and HCP. We anticipate that noninvasive, repeated, and longitudinal cerebral monitoring for the guidance of interventions could be eventually implemented as standard of care in NICUs.